Catalyst-Controlled Site-Selective C-H Functionalizations of Arenes and Heteroarenes

芳烃和杂芳烃的催化剂控制位点选择性 C-H 官能化

基本信息

批准号：
10254416
负责人：
Jin-Quan Yu
金额：
$ 38.56万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-05 至 2024-07-31
项目状态：
已结题

项目摘要

Project Summary Site-selective functionalization of C–H bonds in arenes and heteroarenes can potentially transform the synthesis of bioactive molecules, as it can enable the flexible molecular editing of a scaffold to rapidly generate a diverse set of structures. While C–H bonds proximate to coordinating groups have been successfully activated through its directing effect to form a wide range of C–C and C–X bonds, the majority of C–H bonds in a given molecule are incompatible with this conventional approach. The limitation arises from two factors: 1) distance - the directing effect of a coordinating group diminishes at distances greater than six bonds, and 2) geometry - meta and para positions on arenes are geometrically inaccessible, which greatly restricts the utility of C–H activation in synthesis. These widely recognized challenges escalate with heterocyclic substrates, as heteroatoms coordinate strongly to metal catalysts. This strong binding interaction either limits the utility of C–H activation to proximate sites, or leads to deleterious catalyst poisoning. Therefore, the development of new approaches to achieve selective functionalization of these previously inaccessible C–H bonds is of great value to drug discovery. To achieve the goal of site-selective remote C–H functionalizations of arenes and hetereocycles, we propose three complementary approaches to overcome the two aforementioned challenges. These are 1) the use of transient and catalytic templates, 2) the use of ligand-promoted site-selective C–H activation, and 3) employing a norbornene-mediated relay strategy to expand the first two methods to more distal sites. The first strategy features the use of novel transient directing templates for amine and ketone substrates, as well as employing reversible bifunctional bimetallic directing templates for heterocycles. The second approach is based on our previous finding that phenanthroline-type ligands can promote C-3 selective C–H activation of pyridines, albeit requiring super-stoichiometric amounts of starting material. We propose to redesign this ligand by using additional weak interactions to stabilize the transition states, thereby accelerating the C–H activation reaction. Finally, we propose to utilize norbornenes as a transient mediator to relay the initial remote C–H palladation from the first two approaches to an adjacent, more distal position. The multi-pronged approach presented here fills a major gap in current synthetic methodology. To achieve this overall goal, novel templates, ligands and reagents will be invented. These remote site-selective C–H activation reactions of arenes and heteroarenes will be applied to expedite drug discovery and chemical biology programs in collaboration with the Cravatt and Kelly labs, as well as with Bristol-Myers Squibb.

项目摘要竞技场和杂种中C-H键的位点选择性功能可能有可能转化生物活性分子的合成，因为它可以实现柔性分子编辑脚手架迅速产生各种结构。而C – H的键则与坐标组已通过其导向效应成功激活，形成了宽阔的范围 C – C和C -X键范围，给定分子中的大多数C – H键是不兼容的采用这种传统方法。限制来自两个因素：1）距离 - 指导协调组在距离大于六个键的距离和2）几何形状的影响竞技场上的元和para位置是几何无法访问的，这极大地限制了效用合成中的C – H激活。这些广泛认可的挑战随着杂环的升级底物，作为杂原子与金属催化剂强烈协调。这种强大的结合相互作用要么将C – H激活的效用限制为接近位点，要么导致有害催化剂中毒。因此，开发实现选择性功能化的新方法在这些以前无法访问的C – H键中，对药物发现具有很大的价值。为了实现场地选择性远程C – H功能的目标，杂环，我们提出了三种完整的方法来克服两者关于挑战。这些是1）使用瞬态和催化模板，2）使用配体促进的位点选择性C – H激活，3）使用诺烯烯介导的继电器将前两种方法扩展到更多识别站点的策略。第一个策略以使用新颖的胺和酮底物的瞬态导向模板，并采用可逆的双功能双金属指导模板。第二种方法是基于我们以前的发现，菲交锋配体可以促进C-3选择性C – H 吡啶的激活，尽管需要超大型计量量的起始材料。我们通过使用其他弱相互作用来稳定过渡来重新设计该配体的建议状态，从而加速C – H激活反应。最后，我们建议使用 Norbornenes作为瞬态介体，从前两个中传递最初的遥控C – H palladation 接近相邻，更远端的位置。此处介绍的多管齐的方法当前合成方法论的主要差距。为了实现这一总体目标，新颖的模板，配体和试剂将被发明。这些遥远的位点选择性C – H激活反应竞技场和杂种将应用于加快药物发现和化学生物学与Cravatt和Kelly Labs以及Bristol-Myers Squibb合作的计划。